Palladium-catalyzed arylation of cyanamides

Article abstract of DOI:10.1021/ol203069p

The cross-coupling of alkyl cyanamides with a number of aryl, heteroaryl, and vinyl halide and pseudohalide coupling partners has been developed via a modification of Pd-catalyzed amidation methods. The reactions proceed selectively under mild conditions with reasonable reaction times in moderate to excellent yields.

Full text of DOI:10.1021/ol203069p

ORGANIC
LETTERS
2012
Vol. 14, No. 1
322–325
Palladium-Catalyzed Arylation of
Cyanamides
Ryan M. Stolley, Wenxing Guo, and Janis Louie*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City,
Utah 84112-0850, United States
louie@chem.utah.edu
Received November 15, 2011
ABSTRACT
The cross-coupling of alkyl cyanamides with a number of aryl, heteroaryl, and vinyl halide and pseudohalide coupling partners has been
developed via a modification of Pd-catalyzed amidation methods. The reactions proceed selectively under mild conditions with reasonable
reaction times in moderate to excellent yields.
Incredible progress has been made in metal-catalyzed
cross-coupling methods culminating with the recent
awarding of a Nobel Prize.1 In addition to CꢀC bond
forming reactions, the progress in carbonꢀheteroatom
cross-coupling has become a potent synthetic tool.2 As
such, we were surprised to find that, to the best of our
knowledge, cyanamides have never been the subject of a
cross-coupling study.
Cyanamides are highly versatile NꢀCꢀN building
blocks for a number of organic transformations, primar-
ily in the synthesis of a number of guanidine-containing
molecules, in the synthesis of amidines, and in the synth-
esis of a number of heterocycles.3 These products are
found in innumerable applications: from antiviral4 and
anticancer compounds5 to organometallic ligands6 and to
central nervous system antagonists.7 Apart from cyana-
mide derived compounds, cyanamide moieties themselves
can be found in a number of biologically active com-
pounds. Cyanamides have been utilized as “warheads” in
a number of drug leads for covalent enzyme inhibition.8
Simple cyanamide (H2NCN) itself is under investigation
as an alcohol deterrent agent, and as such, pro-drugs for
its application are also being investigated.9
While a number of methods to synthesize cyanamides
exist, methods for the formation of unsymmetrical aryl/
alkyl and aryl/aryl cyanamides are sparse, particularly
with electron-deficient aryl substituents. Common meth-
ods for the preparation of cyanamides include simple
(1) For information on award, see: http://www.nobelprize.org/nobel_
prizes/chemistry/laureates/2010/press.html.
(6) (a) Xiang, J.; Man, W.-L.; Yiu, S.-M.; Peng, S.-M.; Lau, T.-C.
Chem.;Eur. J. 2011, 17, 13044–13051. (b) Kang, L.-C.; Chen, X.;
Wang, X.-S.; Li, Y.-Z.; Song, Y.; Zuo, J.-L.; You, X.-Z. Dalton Trans.
2011, 40, 5200–5209. (c) Hadadzadeh, H.; Rezvani, A. R.; Esfandiari, H.
Polyhedron 2008, 27, 1809–1817.
(7) (a) Biegon, A.; Gibbs, A.; Alvarado, M.; Ono, M.; Taylor, S.
Synapse 2007, 61, 577–586. (b) Imtiaz, A.; Bose, S. K.; Pavese, N.;
Ramlackhansingh, A.; Turkheimer, F.; Hotton, G.; Hammers, A.;
Brooks, D. J. Brain 2011, 134, 979–986.
(2) For general references and recent reviews for metal-catalyzed
cross-coupling: (a) A. de Meijere, A.; Diederich, F. Metal-Catalyzed
Cross-Coupling Reactions; Wiley-VCH: Weinheim, 2004; Vols. 1 and 2.
(b) Negishi, E.; Wang, G. In Science of Synthesis; Rawal, V., Kozmin, K.,
Eds.; Thieme: New York, Stuttgart, 2009; Vol. 46, pp 239ꢀ351. (c) Negishi,
E.; Wang, G. In Science of Synthesis; Jacobsen, E. N., de Meijere, A., Eds.;
Thieme: New York, Stuttgart, 2010; Vol. 47, pp 909ꢀ1016. (d) Alonso,
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D. A.; Najera, C. In Science of Synthesis; de Meijere, A., Ed.; Thieme: New
York, Stuttgart, 2009; Vol. 47a, pp 439ꢀ479. (e) Jana, R.; Pathak, T. P.;
Sigman, M. S. Chem. Rev. 2011, 111, 1417–1492. (f) Schlummer, B.;
Scholz, U. Adv. Synth. Catal. 2004, 346, 1599–1626. (g) Senra, J. D.;
Aguiar, L. C. S.; Simas, A. B. C. Curr. Org. Synth. 2011, 8, 53–78.
(3) For leading sources: (a) Nekrasov, D. D. Russ. J. Org. Chem.
2004, 40, 1387–1402. (b) Nekrasov, D. D. Chem. Heterocycl. Compd.
2004, 40, 1107–1123.
(4) Kumar, R.; Rai, D.; Sharma, S. K.; Saffran, H. A.; Blush, R.;
Tyrrell, D. L. J. J. Med. Chem. 2001, 44, 3531–3538.
(5) Lu, Y.; Li, C.-M.; Wang, Z.; Chen, J.; Mohler, M. L.; Li, W.;
Dalton, J. T.; Miller, D. D. J. Med. Chem. 2011, 4678–4693.
(8) Guay, D.; Beaulieu, C.; Percival, M. D. Curr. Top. Med. Chem.
2010, 10, 708–716.
(9) (a) Shirota, F. N.; Stevens-Johnk, J. M; DeMaster, E. G.; Nagasawa
H. T. J. Med. Chem. 1997, 40, 1870–1875. (b) Closon, C.; Didone, V.;
Tirelli, E.; Quertemont, E. Alcohol.: Clin. Exp. Res. 2009, 33, 2005–
2014.
(10) (a) Kim, J.-J.; Kweon, D.-H.; Cho, S.-D.; Kim, H.-K.; Jung,
E.-Y.; Lee, S.-G.; Falck, J. R.; Yoon, Y.-J. Tetrahedron 2005, 61, 5889–
5894. (b) Maezaki, N.; Furusawa, A.; Uchida, S.; Tanaka, T. Hetero-
cycles 2003, 59, 161–167. (c) Wu, Y.-Q.; Limburg, D. C.; Wilkinson,
D. E.; Hamilton, G. S. Org. Lett. 2000, 2, 795–797.
r
10.1021/ol203069p
Published on Web 12/05/2011
2011 American Chemical Society

substitution of cyanogen bromide or more exotic cyanat-
ing agents.10 However, the reduced nucleophilicity of aryl
or diaryl amines (particularly with electron-withdrawing
groups) can lead to poor yields. A common alternative,
the Von Braun reaction,11 while effective, requires extra-
neous formation of a trisubstituted amine, thereby po-
tentially leading to moderate to low yields. As an alter-
native, more-direct approach, we believed a mild and
efficient cross-coupling method might be utilized to
greatly expand the inventory of available cyanamides.
Table 1. Ligand Screen for the Pd-Catalyzed Arylation of Butyl
Cyanamide (1a)a
Figure 1. Promixal and terminal cyanamide coordination
equilibrium.
Containing both nucleophilic and electrophilic sites
within the same molecule, cyanamides have a somewhat
unique reactivity. The basicity of the amino nitrogen is
strongly reduced due to the conjugation of its lone pair
with the CꢀN triple bond. As such cyanamides exist as
both an N-cyanoamine and diimide tautomers (Figure 1),
while the N-cyanoamine form dominates; in a few reac-
tions (e.g., silylation, protonation, metal coordination,
etc.) the diimide form appears to dominate.3,6 Further-
more, monsubstituted cyanamides are prone to thermal
trimerization. In addition, trimerization occurs in both
Lewis acidic and basic conditions to form melamine and
isomelamine derivatives.12 Even as much, we hypothe-
sized that Pd-catalyzed aryl amidation conditions may be
mild enough to facilitate coupling. Herein, we report a
general Pd-catalyzed method for the cross-coupling of
alkyl cyanamides with a number of aryl, heteroaryl, and
vinyl halides as well as pseudohalides.
a Reaction conditions: 1a (0.25 M in tBuOH), 2a (1 equiv), Cs2CO3
(1.5 equiv), Pd2dba3 (2.5 mol %), Ligand (7.5 mol %), 100 °C, 12 h.
b Determined via GC using naphthalene as an internal standard. c 10 mol %
ligand used. d Isolated yield. e Trace.
conversion of starting material but also afforded only trace
amounts of the desired cross-coupling product (3). Further
evaluation of the reaction conditions led to the following
optimized conditions: cyanamide (1.1 equiv), aryl halide
(1 equiv), Cs2CO3 (1.5 equiv), Pd2dba3 (2.5 mol %), and
t
tBuXPhos (7.5 mol %) in AmylOH at 60 °C for 3 h.
Pd(OAc)2 (5 mol %), instead of Pd2dba3, is not a competent
precatalyst. However, when PhB(OH)2 (5mol%) isaddedas
a sacrificial reductant, cross-coupling does occur, although
yields are slightly lower than when Pd2dba3 is employed.
Initial investigations focused on the Pd-catalyzed cross-
coupling of butyl cyanamide (1a) and bromobenzene (2a,
eq 1, Table 1). Our survey of phosphine ligands revealed that
the use of tBuXPhos resulted in full conversion of bromoben-
zene and formation of the desired product (3) in 55% yield.
Interestingly, XPhos, BrettPhos, and XantPhos ligands,
(13) Where general XPhos motif = 2-disubstituted-phosphino-
Rx-substituted-20,40,60-triisopropylbiphenyl. (a)Fors, B. P.;Dooleweerdt,
K.; Zeng, Q.; Buchwald, S. L. Tetrahedron 2009, 65, 6576. (b) Ikawa, T.;
Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
13001.
t
which are more effective than BuXPhos in analogous
Pd-catalyzed amidation reactions,14 not only gave incomplete
(11) (a) Von Braun, I. J.; Heider, K.; Muller, E. Ber. 1918, 51, 281.
(b) Cressman, H. W. J. Org. Synth. 1955, 3, 608.
(14) Where XantPhos = 4,5-bis(diphenylphosphino)-9,9-dimethyl-
xanthene. (a) Hicks, J. D.; Hyde, A. M.; Martinez-Cueza, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2009, 131, 16720–16734. (b) Yin, J.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 6043–6048. (c) Yin, J.; Buchwald, S. L.
Org. Lett. 2000, 2, 1101–1104.
(12) (a)Pankratov, V. A.;Chesnokova, A. E.Ups. Khimii 1989, 58, 1528–
1548. (b) Korshak, V. V.; Kutepov, D. F.; Pankratov, V. A.; Antsiferova,
N. P.; Vinogradova, S. V. Zhur. Vsesoy. Khimi. Obs.: Mendeleeva 1974, 19,
472–3. (c) Wu, Y.-Q. In Science of Synthesis; Ley, S. V., Knight, J. G., Eds.;
Thieme: New York, Stuttgart, 2005; Vol. 18, pp 17ꢀ63.
(15) Where BrettPhos = 2-(dicyclohexylphosphino)3,6-dimethoxy-
20,40,60-triisopropyl-1,10-biphenyl. See also ref 13.
Org. Lett., Vol. 14, No. 1, 2012
323

tert-butyl cyanamide leads to decreased yields (entry 17).
Negative steric effects are further observed in the lack of
reaction between both o-bromotoluene and mesityl bro-
mide with1a(entries15ꢀ16) aswell astetrahydronaphthyl-
cyanamide 1g and previously productive 2f (entry 21).
Bulky coupling substrates in combination with the large
tBuXPhos ligand may force unproductive diimide coordi-
nation, effectively killing the catalyst (Figure 1).
Table 2. Cross-Coupling Substrate Scopea
Figure 2. Cross-coupling of 1a with heteroaryl bromides.
Heterocycles were also found to be viable substrates.
Coupling of 3-bromopyridine occurred smoothly, leading
to 20 in excellent yield (eq 3, Figure 2). Previous attempts
to achieve cyanate 2-aminopyridines with cyanogen bromide
or N-cyanoimidazole led to presumed cyanation at the
pyridine nitrogen, followed by rapid decomposition. As such,
we were delighted to find coupling of 2-bromopyridine with
butyl cyanamide proceeded to afford 21 in excellent yield.
Free amines are amenable to reaction conditions if confor-
mationally restrained from nucleophilic addition into the
nitrile as seen in the coupling of 5-bromoindole (22).
In addition, cyanamides react preferentially in the presence
of amides as seen in the coupling between the exclusive
coupling of 4-bromobenzamide and butyl cyanamide (eq 4).
The coupling of vinyl bromides and vinyl triflates afforded
rare vinyl cyanamides, albeit in decreased yields (eqs 5ꢀ6).
a Reaction conditions: cyanamide (1.1 equiv), aryl halide (1 equiv),
Cs2CO3 (1.5 equiv), Pd2dba3 (2.5 mol %), tBuXPhos (7.5 mol %), 60 °C,
3 h. b All yields are average isolated yields from experiments run in at
least duplicate. c Pd2dba3 (3.5 mol %), tBuXPhos (10.5 mol %), 60 °C, 6 h.
Our cross-coupling conditions are amenable with a num-
ber substituted aryl bromides, triflates, and iodides (eq 2,
Table 2). Furthermore, the order of reactivity follows
ArBr > ArOTf > ArI (entries 1ꢀ2, 5ꢀ8). However, reac-
tions with aryl chlorides led to catalyst poisoning (by an, as of
yet, undetermined mechanism) and resulted in minimal
(<10%) conversion (entries 3ꢀ4). Selective coupling can
be obtained as seen in the reaction of butyl cyanamide (1a)
with 1-bromo-4-fluoro-benzene, which leads to formation of
N-butyl-N-(4-fluorophenyl)cyanamide (7, entry 9). While
the conditions are effective with most aryl halides screened,
yields are generally higher with activated (i.e., electron-
deficient) aryl halides (entries 10ꢀ12). For reactions with
electron-rich aryl halides, yields are generally depressed, and
extended reaction times and higher catalyst loadings are
required (entries 13ꢀ14). Other alkyl cyanamides, such
as benzyl and cyclohexyl cyanamide, are also excellent
substrates (entries 18 and 20, respectively). However, bulky
In conclusion, we have developed a mild and effi-
cient method for the Pd-catalyzed arylation of alkyl
324
Org. Lett., Vol. 14, No. 1, 2012

cyanamides. The reaction is amenable to electron-
donating and-withdrawing aryl halides as well as het-
eroaryl halides and pseudohalides. In addition, vinyl
halides are also able to be cross-coupled with cyana-
mides to yield vinyl cyanamides in moderate yields.
Mechanistic investigations are ongoing in our labo-
ratories.
Acknowledgment. The NSF (0911017) is acknowledged
for financial support. W.G. thanks Technische Universitat
Braunschweig and Deutscher Akademischer Austausch
Dienst (DAAD) for a fellowship.
Supporting Information Available. Experimental de-
tails, 1H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 1, 2012
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